WO2020212895A1 - Procédé et appareil permettant de faciliter la liaison de la protéine gap à la protéine ras mutante par des agents moléculaires pour le traitement de cancers liés à une mutation ras - Google Patents

Procédé et appareil permettant de faciliter la liaison de la protéine gap à la protéine ras mutante par des agents moléculaires pour le traitement de cancers liés à une mutation ras Download PDF

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WO2020212895A1
WO2020212895A1 PCT/IB2020/053596 IB2020053596W WO2020212895A1 WO 2020212895 A1 WO2020212895 A1 WO 2020212895A1 IB 2020053596 W IB2020053596 W IB 2020053596W WO 2020212895 A1 WO2020212895 A1 WO 2020212895A1
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carboxamide
derivatives
heterocyclic
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Vince Grolmusz
Beata Grolmuszne Vertessy
Jozsef Timar
Jozsef Tovari
Attila KIGYOS
Kinga NYIRI
Ivan RANDELOVIC
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/50—Molecular design, e.g. of drugs
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • G16B5/30—Dynamic-time models

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  • Mutated genes may lead to cancer development in human tissues. While more than 600 cancer causing genes (or oncogenes) are known today (listed in the Catalogue of Somatic Mutations In Cancer, https://cancer.sanger.ac.uk/cosmic ), numerous mutations are connected to the RAS gene, whose mutations are found in approximately 25% of all human tumors [1] Cancers, caused by RAS mutations, are some of the most difficult to treat, and they are frequently excluded from chemotherapeutic attacks as hopeless cases [2]
  • The“undruggability” of the RAS protein relates to the lack of the binding cavities on the molecular surface, important in the oncogenic process [4,5]
  • RAS proteins there are three RAS proteins: KRAS, NRAS and HRAS; the protein KRAS is the most frequently mutated in cancers (>85%). Therefore, KRAS is one of the most important targets of the drug development efforts.
  • the oncogene mutations have a steric structure that does not allow the RAS-GAP binding.
  • the mutant KRAS has several allelic variants, the most frequent one is G12D.
  • Variant G12C is the most frequent in lung cancer but G12D is by far the most frequent allelic variant in any other cancer types placing it into the front of anti-RAS drug developments.
  • the KRAS-G12D mutant and the GAP protein are glued together by small molecules, disclosed here.
  • the efficacy of such small molecules in killing cancerous cells are demonstrated in human cell cultures.
  • the oncogenic effects of RAS mutations are due to the steric changes, relative to the non- mutated (wild type) RAS molecules.
  • the wild-type RAS molecule binds the GAP (GTPase- activating protein), and this binding terminates a signaling cascade. If the GAP is not bound to the mutated RAS, the signaling cascade is not terminated, and the result is an un-controlled cell growth factor production process [9]
  • FIG. 1 schematically shows the configuration of the non-mutated (wild type) RAS molecule (101), complexedwith the GAP molecule (102).
  • FIG. 2 schematically shows the mutated RAS molecule (201) with the steric anomaly (203), which prevents the functional binding of the GAP molecule (202).
  • FIG. 3 schematically shows the RAS (301) GAP (302) complex, which was formed with the presence of the steric anomaly (303), by the gluing effect of small molecule (304). If the RAS- GAP complex is formed leading to hydrolysis of RAS-bound GTP to GDP, then the signaling pathway [9] is terminated. Therefore, the cancerous transformation will not happen. Note that the small molecule (304) is bound to both RAS (301) and GAP (302) molecules. The 30 years of unsuccessful trials for finding drugs, which bind to RAS [4,5], is circumvented by the new method, which identifies small molecules (like 304), binding to both RAS (301) and GAP (302), efficiently gluing them, and therefore, terminating the signaling pathway.
  • FIG. 4 discloses our novel method of identifying new small molecules, which are able of gluing the mutated RAS and the GAP molecules, and, consequently, terminating the signaling pathway.
  • the method comprises the following steps:
  • the RAS-GAP surface distance is chosen to be 5 A. In another particular embodiment, the distance is 6 A.
  • the GAP-RAS configuration constructed in (401), serves as a receptor for high- throughput computerized molecular docking process, docking millions of small molecules to the receptor.
  • the members of the ZINC small molecule database [10] are docked to the receptor.
  • the best scored molecules are synthesized or acquired from vendors, and their anti cancer activity is verified in human cancer cell cultures. The molecules with the best efficacy are identified.
  • FIG. 5 discloses one particularly advantageous embodiment of molecular glues, which connects G12D mutant KRAS and GAP molecules.
  • the representative member of this molecular family is shown in the figure, referred to as “molecule 501”.
  • Molecule 501 has a strong differential activity against the G12D mutated cancer cells.
  • FIG. 6 discloses another particularly advantageous embodiment of molecular glues, which connects G12D mutant KRAS and GAP molecules.
  • the representative member of this molecular family is shown in the figure, referred to as “molecule 601”.
  • Molecule 601 has a strong differential activity against the mutant KRAS G12D cell line.
  • the IC15 value with PANC-1 is 4.5 nM, with BxPC3 181 nM; i.e., molecule 501 has more than 40 times higher activity against the G12D mutant PANC-1 cell line.
  • the IC25 value with PANC-1 is 50 nM, with BxPC3 550 nM; i.e., molecule 501 has more than 10 times higher activity against the mutant PANC-1 cell line.
  • the IC15 value with PANC-1 is 0.68 mM, with BxPC3 3.10 pM; i.e., molecule 601 has more than 4 times higher activity against the mutant PANC-1 cell line.
  • the IC25 value with PANC-1 is 1.59 pM, with BxPC3 4.35 pM; i.e., molecule 601 has more than 2.5 times higher activity against the mutant PANC-1 cell line.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Crystallography & Structural Chemistry (AREA)
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Abstract

L'invention concerne (i) de nouveaux composés de formule générale (II) et (ii) de nouveaux composés de formule générale (IV), (iii) des compositions pharmaceutiques contenant l'un quelconque de ces composés en tant que principes actifs, et (iv) des préparations de ces composés, R étant défini dans les revendications. Les nouveaux composés sont efficaces pour prévenir et/ou traiter des maladies provoquées par les mutations KRAS G12D, y compris des cancers et d'autres maladies.
PCT/IB2020/053596 2019-04-16 2020-04-16 Procédé et appareil permettant de faciliter la liaison de la protéine gap à la protéine ras mutante par des agents moléculaires pour le traitement de cancers liés à une mutation ras Ceased WO2020212895A1 (fr)

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US62/834,498 2019-04-16

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2023138589A1 (fr) * 2022-01-20 2023-07-27 思路迪生物医药(上海)有限公司 Dérivé de pyrimidine hétérocyclique à cinq chaînons et son utilisation en tant qu'inhibiteur de mutation pan-kras
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US12527795B2 (en) 2018-09-10 2026-01-20 Mirati Therapeutics, Inc. Compositions of adagrasib and mTOR inhibitors and methods of treatment therewith

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WO2012035423A1 (fr) * 2010-09-15 2012-03-22 Katholieke Universiteit Leuven, K.U. Leuven R&D Activité anticancéreuse de nouveaux hétérocycles bicycliques
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12527795B2 (en) 2018-09-10 2026-01-20 Mirati Therapeutics, Inc. Compositions of adagrasib and mTOR inhibitors and methods of treatment therewith
US12485122B2 (en) 2018-09-10 2025-12-02 Mirati Therapeutics, Inc. Combination of palbociclib and adagrasib for lung cancer
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
US12336995B2 (en) 2018-09-10 2025-06-24 Mirati Therapeutics, Inc. Combination therapies
US12377101B2 (en) 2018-12-05 2025-08-05 Mirati Therapeutics, Inc. Combination therapies
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US12304915B2 (en) 2019-12-20 2025-05-20 Mirati Therapeutics, Inc. SOS1 inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US12286431B2 (en) 2020-09-11 2025-04-29 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12281113B2 (en) 2020-09-11 2025-04-22 Mirati Therapeutics, Inc. Crystalline forms of a KRas G12C inhibitor
US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
WO2023138589A1 (fr) * 2022-01-20 2023-07-27 思路迪生物医药(上海)有限公司 Dérivé de pyrimidine hétérocyclique à cinq chaînons et son utilisation en tant qu'inhibiteur de mutation pan-kras
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer

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